CN104428296B

CN104428296B - The method for preparing 3,5 two 1,2,4 oxadiazoles of substitution

Info

Publication number: CN104428296B
Application number: CN201380033222.7A
Authority: CN
Inventors: W·H·米勒; C·R·格拉哈姆; D·L·布朗
Original assignee: Monsanto Co
Current assignee: Monsanto Co
Priority date: 2012-07-02
Filing date: 2013-07-02
Publication date: 2017-11-14
Anticipated expiration: 2033-07-02
Also published as: US9040711B2; AU2013286860A1; BR112014032956B1; DK2867230T3; MX2014015794A; US20150225382A1; EP2867230B1; US9273037B2; WO2014008257A2; CA2876215A1; BR112014032956A2; UA114915C2; EP2867230A2; CN104428296A; EP2867230A4; AU2013286860B2; AR091655A1; US20140039197A1; ZA201409000B; WO2014008257A3

Abstract

Provided herein is the methods for preparing 3,5 two 1,2,4 oxadiazoles of substitution and its salt, it includes making N hydroxyamidines and acyl chlorides to be reacted in the reactant mixture comprising organic solvent and aqueous alkali not miscible with water under relatively low reaction temperature.

Description

Prepare the method that 3,5- bis- substitutes -1,2,4- oxadiazoles

Technical field

Provided herein is prepare bioactivity 3,5- bis- substitute -1,2,4- oxadiazoles or its salt method , Suo Shu oxadiazoles or Its salt is applied to for example control nematode.

Background of invention

1,2,4- oxadiazole and specifically 3,5- bis- substitute -1,2,4- oxadiazoles to be illustrated in medicine and agricultural neck There is bioactivity in domain.For example, 3,5- bis- substitutes -1,2,4- oxadiazoles to be disclosed as disease and suppressed and the therapeutic agent (U.S. Patent the 6th, 992,096), the therapeutic agent (disclosing US 200,5/0,075,375 A1) of hepatitis C, and in agriculture Nematode control (disclosing US 200,9/0,048,311 A1) is carried out in industry.

3,5- bis- substitute -1,2,4- oxadiazoles to prepare in many ways.A kind of method is via making aryl amide oxime - 1,2,4- oxadiazoles are substituted (to disclose US 200,8/0,269,236 A1, U.S. Patent No. to prepare 3,5- bis- with acyl chloride reaction No. 7,678,922, US 200,8/0,113,961 A1, JP 2008120794 and Bioorg.Med Chem are disclosed Lett.19,4410).Another kind is used for preparation 3,5- bis- and substitutes the method for -1,2,4- oxadiazoles to be to make benzoyl amidoxime or propionyl Amidoxime and carboxylic acid or ester reaction (WO 2011/141326, WO 2012/012477 and WO 2011/085406).It is other to reach 3, 5- bis- substitutes the path of 1,2,4- oxadiazoles to include making benzamide (disclose US 2010/ with the reaction of Weinreb acid amides 0048648 No. A1) and the halogen of hydroxyl penta is reacted (U.S. Patent No. 3,211,742) with nitrile.

It is used to prepare the method that 3,5- bis- substitutes -1,2,4- oxadiazoles although existing, combined coefficient can be caused higher Alternate paths be very desirable.Specifically, the synthetic method with less separating step and/or solvent can be with It is more efficient and more cheap.In addition, reduce and/or eliminate solids treatment, reduce the reaction time and/or using less The method of reaction intermediate can substantially reduce the capital equipment expenditure in extensive manufacture.Finally, using relatively mild reaction Condition (such as lower temperature) can prevent wanted intermediate and product degradation, produce less unwanted accessory substance and it is final most Good product purity overview.

Reference to any of the above bibliography is not construed as recognizing the prior art that the bibliography is the application.

Brief summary of the invention

Provided herein is the method that preparation 3,5- bis- substitutes -1,2,4- oxadiazoles and its salt.For example, side as described herein Method is applied to formula (Ia) or 3, the 5- bis- of (Ib) substitutes -1,2,4- oxadiazoles,

Wherein Ar¹Phenyl, pyridine radicals, pyrazolyl, oxazolyl Huo isoxazolyls, its each can optionally independently by The substitution of one or more substituents, the substituent for example alkyl, alkylhalide group, alkoxy, alkyl groups in the halogenalkoxy, halogen, acyl group, ester and Nitrile；And Ar²It is thienyl, furyl, oxazolyl, isoxazolyls or phenyl, it each can be optionally independently by one Or multiple substituent substitutions, the substituent such as fluorine, chlorine, CH₃And OCF₃.In one embodiment, methods described includes dividing Do not make following：The N- hydroxyamidines or its tautomeric form of formula (IIa) or (IIb), wherein Ar¹And Ar²As hereinbefore defined,

Respectively with formula (IIIa) or the acyl chlorides of (IIIb), wherein Ar¹And Ar²As hereinbefore defined,

Reacted in the reactant mixture comprising organic solvent and aqueous alkali not miscible with water, and it is described The temperature of reactant mixture is no more than about 85 DEG C.

Detailed description of the invention

This disclosure relates to improved preparation 3,5- bis- substitutes the method for -1,2,4- oxadiazoles and its salt.Methods described it is each Kind embodiment realizes larger manufacture convenience, the reaction time circulation compared with mild reaction conditions, reduction, among less reaction Body and/or the capital equipment demand substantially reduced.

In general, method described herein is applied to formula (Ia) or 3, the 5- bis- of (Ib) substitutes -1,2,4- Evil bis- Azoles or its salt,

Wherein Ar¹Phenyl, pyridine radicals, pyrazolyl, oxazolyl Huo isoxazolyls, its each can optionally independently by One or more substituent substitutions.In one embodiment, Ar¹Optionally independently it is selected from by one or more by with the following group Into group substituent substitution：Alkyl, alkylhalide group, alkoxy, alkyl groups in the halogenalkoxy, halogen, acyl group, ester and nitrile, it can each appoint Selection of land is independently substituted.In one embodiment, Ar¹Optionally independently it is selected from what is consisted of by one or more The substituent substitution of group：Halogen, CF₃、CH₃、OCF₃、OCH₃, CN and C (H) O.Ar²It is thienyl, furyl, oxazolyl, Yi Evil Oxazolyl or phenyl, it each can optionally independently be substituted.In one embodiment, Ar²Optionally independently by one Individual or multiple substituent substitutions selected from the group consisted of：Fluorine, chlorine, CH₃And OCF₃。

For example, in some embodiments, Ar¹It is unsubstituted phenyl.In other embodiments, Ar¹Be by Mono-substituted phenyl, wherein substituent are halogens.In other embodiments, Ar¹It is by dibasic chlorine alkyl phenyl.One In a little embodiments, Ar²It is substituted thienyl or substituted furyl.In some embodiments, Ar²It is not taken The thienyl in generation or unsubstituted furyl.

In some embodiments, 3,5- bis- substitutes -1,2,4- oxadiazoles to be formula (Ia-i) compound or its salt,

Wherein R¹And R⁵Independently selected from hydrogen, CH₃、F、Cl、Br、CF₃And OCF₃；R²And R⁴Independently selected from hydrogen, F, Cl, Br And CF₃；R³Selected from hydrogen, CH₃、CF₃、F、Cl、Br、OCF₃、OCH₃, CN and C (H) O；R⁷And R⁸Independently selected from hydrogen and fluorine；R⁹It is selected from Hydrogen, F, Cl, CH₃And OCF₃；And E is O, N or S.

According to 3,5- bis- prepared by the disclosure non-limiting examples of -1,2,4- oxadiazoles can be substituted to include formula (Ia- Ii 3- phenyl -5- (2- thienyls) -1), 2,4- oxadiazoles,

3- (4- the chlorphenyls) -5- (2- furyls) -1 of formula (Ia-iii), 2,4- oxadiazoles,

3- (4- chloro-2-methyls the phenyl) -5- (2- furyls) -1 of formula (Ia-iv), 2,4- oxadiazoles,

3- phenyl-the 5- (2- furyls) -1 of formula (Ia-v), 2,4- oxadiazoles,

3- (4- bromophenyls) -5- (furans -3- bases) -1 of formula (Ia-vi), 2,4- oxadiazoles, and

3- (2,4- difluorophenyl)-(thiene-3-yl) -1 of formula (Ia-vii), 2,4- oxadiazoles.

In other embodiments, 3,5- bis- substitutes -1,2,4- oxadiazoles to be formula (Ib-i) compound or its salt,

Wherein R¹To R⁵、R⁷To R⁹With E as hereinbefore defined.

According to 3,5- bis- prepared by the disclosure other non-limiting examples of -1,2,4- oxadiazoles can be substituted to include formula (Ib-ii) 3- (thiophene -2- bases) -5- (p-methylphenyl) -1,2,4- oxadiazoles,

5- (3- chlorphenyls) -3- (thiophene -2- bases) -1 of formula (Ib-iii), 2,4- oxadiazoles, and

5- (4- chloro-2-methyls the phenyl) -3- (furans -2- bases) -1 of formula (Ib-iv), 2,4- oxadiazoles.

According to other representative 3,5- bis- prepared by the disclosure -1,2,4- oxadiazoles can be substituted to be described in and disclose US In 2009/0048311 No. A1, its whole, which includes, to be incorporated herein by reference.

In various embodiments, methods described is following including making：Formula (IIa) or (IIb) N- hydroxyamidines or its change Isomeric form,

Wherein Ar¹And Ar²As hereinbefore defined, respectively with formula (IIIa) or the acyl chlorides of (IIIb),

Wherein Ar¹And Ar²As hereinbefore defined.The condensation reaction of N- hydroxyamidines and acyl chlorides is including organic solvent and buck Carried out in the reactant mixture of solution.Be not bound by it is specific theoretical in the case of, in some embodiments, N- hydroxyamidines with The reaction of acyl chlorides is considered as production (IVa) or oxime ester intermediate, its salt or its tautomeric form of (IVb),

Wherein Ar¹And Ar²As hereinbefore defined.As described in greater detail below, the presence of aqueous alkali contributes to oxime ester to exist Cyclisation substitutes -1,2,4- oxadiazole products to produce 3,5- bis- under relative low temperature.In one embodiment so that condensation and/ Or cyclization occurs directly to up to final 3,5- bis- and substitutes -1,2,4- oxadiazole products, among isolated or purified oxime ester Body.In other embodiments, oxime can be separated and/or purified before forming 3,5- bis- and substituting -1,2,4- oxadiazole products Ester intermediate or one part.

According to various embodiments, selected based on one or more criterions to form the solvent of reactant mixture, to have Help simplification and the macroeconomic of methods described.In some embodiments, organic solvent used can make formula (IIa) or (IIb) N- hydroxyamidines and formula (Ia) or (Ib) 3,5- bis- substitutes -1,2,4- oxadiazole products to dissolve.In some embodiments In, organic solvent equally can dissolve formula (IVa) or (IVb) intermediate oxime ester.Using organic solvent so that N- hydroxyamidines Initial substance and oxime ester intermediate and 3,5- bis- substitute the dissolving of -1,2,4- oxadiazole products to reduce or eliminate to separating N- hydroxyls Base amidine and/or the needs of oxime ester, and reduce or eliminate cyclisation with formed 3,5- bis- substitute -1,2,4- oxadiazole products it The preceding needs to solvent switching.In various embodiments, organic solvent can advantageously to by N- hydroxyamidines reactant from One reaction vessel is transferred to another reaction vessel.In some cases, organic solvent not miscible with water is used to separate Formula (IIa) or (IIb) N- hydroxyamidines and manufacture 3,5- bis- substitute -1,2,4- oxadiazole products.Using not miscible with water Organic solvent causes the aqueous phase and organic phase of separable reactant mixture, its realize N- hydroxyamidines reactant from a container to The more easily transfer of another container, and help to reclaim final 3,5- bis- and substitute -1,2,4- oxadiazole products, following article It is explained in more detail.In addition, in one embodiment, organic solvent not miscible with water forms azeotropic mixture with water.Azeotropic Thing is helped to via for example evaporating or distilling removal solvent, so that separation of intermediates oxime ester or 3,5- bis- substitute -1,2, 4- oxadiazole products.Or more than one organic solvent can be used, such as in the oxime ester for manufacturing formula (IVa) or (IVb) The solvent not miscible with water of mesosome；Substitute miscible molten of the water of -1,2,4- oxadiazole products with for manufacturing 3,5- bis- Agent.The non-limiting examples of suitable organic solvent include acetone, 2- butanone, ethyl acetate, isopropyl acetate, butyl acetate, Chloroform, dichloromethane, diethyl ether, methyl t-butyl ether, butyl oxide, anisole, tetrahydrofuran, 2- methyltetrahydrofurans, diformazan Benzene and toluene.In various embodiments, organic solvent includes acetone, 2- butanone, tetrahydrofuran, 2- methyltetrahydrofurans or second Acid butyl ester.In one embodiment, organic solvent is butyl acetate or 2- methyltetrahydrofurans.

Aqueous alkali includes a kind of chemical reagent, and the sour accessory substance of its condensation reaction between N- hydroxyamidines and acyl chlorides is anti- Should.In addition, in the case where being not bound by any particular theory, it is believed that aqueous alkali has been catalyzed formula (IVa) or the oxime ester of (IVb) Cyclisation substitutes -1,2,4- oxadiazoles with 3, the 5- bis- of production (Ia) or (Ib).

" aqueous alkali " is in the highly basic or alkali for being defined herein as completely or almost completely decomposing in water.Can be with using strong basis Advantageously cause the reaction time faster.In some embodiments, aqueous alkali is the alkalescence comprising alkali metal or alkaline-earth metal Alkali, and it is decomposed to form hydroxide ion in aqueous.The non-limiting examples of suitable aqueous alkali include inorganic base The aqueous solution, the inorganic base such as sodium hydroxide, potassium hydroxide, lithium hydroxide, calcium hydroxide and its mixture.In a reality Apply in scheme, the aqueous alkali being added in reactant mixture includes base reagent with about 5 weight % to about 60 weight % concentration. In an exemplary embodiment, aqueous alkali is alkaline hydrated oxide, and its condensation between N- hydroxyamidines and acyl chlorides is anti- The sour byproduct reaction answered is to form water (water is only formed from hydroxide bases) and salt.

According to an embodiment, reactant mixture optionally includes phase transfer catalyst.Phase transfer catalyst is a kind of Chemical reagent, it contributes to migration of the reactant from aqueous phase into organic phase, or vice versa it is as the same.Therefore, using phase transfer catalysis (PTC) Agent can advantageously cause the reaction time comparatively fast and conversion or yield are higher.

In various embodiments, phase transfer catalyst is quaternary ammonium salt, phosphonium salts or crown ether.Suitable phase transfer catalyst Non-limiting examples include TBAH, benzyl trimethylammonium hydroxide, TBAB, tetrabutyl chlorination Ammonium, tetrabutylammonium iodide, Si butyl phosphonium bromide and 4-butyl phosphonium chloride.In one embodiment, phase transfer catalyst is four Butyl ammonium hydroxide.In one embodiment, phase transfer catalyst is with the aqueous solution (such as 40 weight % of phase transfer catalyst The aqueous solution) form is added in reactant mixture, make it that ultimate density is about 0.5-3 moles % in terms of acyl chlorides, more preferably In terms of acyl chlorides in the range of about 0.5-1.5 moles % or about 1.5-2 moles %.

In an embodiment of methods described, the N- hydroxyamidines of formula (IIa) or (IIb) is dissolved in and can not be mixed with water In molten organic solvent, and solution is introduced into reaction vessel.Addition water, at least a portion aqueous alkali mutually turn with optional Shifting catalyst is into reaction vessel.This can be while and/or sequentially.This results in two-phase reaction mixture, wherein N- Hydroxyamidines is remained dissolved in the organic phase comprising organic solvent not miscible with water.The acyl of adding type (IIIa) or (IIIb) The aqueous alkali of chlorine reactant and any remainder is into reaction vessel.Acyl chlorides and remainder can simultaneously or sequentially be added Aqueous alkali.In one embodiment, to equal or exceed the amount of acyl chlorides, to be added to reaction mixed in mol for N- hydroxyamidines In compound.Additional water whenever can be added during the course of the reaction into reactant mixture.

In some embodiments, mixture can be stirred.In other embodiments, groove for example can continuously stirred Continuously reacted in reactor.

In order to increase reaction rate and obtain the acceptable reaction time, the concentration of alkali is excellent in the aqueous phase of reactant mixture Selection of land is enough to obtain at least about 8, at least about 9 or at least about 10 pH, and higher pH causes reaction rate to increase.For example, exist In one embodiment, about 12 to about 13 pH is to cause the increased pH scopes of reaction rate.It can lead to during methods described Cross the pH for adding extra aqueous alkali into reactant mixture to maintain or increase aqueous phase.

The temperature of reactant mixture is about 25 DEG C to about 85 DEG C.In some embodiments so that the temperature of reactant mixture Degree rises as the result of exothermic heat of reaction, and preferably about 55 DEG C to about 75 DEG C.Reaction can be caused in the absence of applying It is added under the outside heat of reactant mixture and occurs, but the heat from foreign source can be supplied on demand to remain to want anti- Answer temperature and speed.

The adding rate of acyl chlorides and remaining aqueous alkali depends on reaction scale and controls the ability of temperature.For example, The adding rate of acyl chlorides can be between 30 minutes and 4 hours.Advantageously so that result of the reactant mixture as exothermic heat of reaction And heat, as described above, and about 30 minutes can be maintained at about 55 DEG C to about 75 DEG C by about 2 hours to cause reaction Completely.After completion of reaction, typically so that aqueous phase separates with organic phase in heat.In some embodiments, can be optional Ground neutralizes aqueous phase to relatively low pH (such as dropping below about 9 pH) to help subsequent formulation 3, and 5- bis- substitutes -1,2,4- Evil Diazole product.In some embodiments, a part of aqueous phase is removed from reactant mixture, and had by evaporating or distilling removal Solvent.When solvent levels are low, the azeotropic mixture or pairing help of water and solvent displace trace solvent.Can under atmospheric pressure or Distilled under vacuo.Additional water can be added into reactant mixture, its volume be enough to replace the solvent that is distilled and Help to separate final product.- 1,2,4- oxadiazole products are substituted to be precipitated in water layer as solvent evaporates, 3,5- bis-, in water Slurry of solids is produced in layer.When having removed substantial all solvents, can be reclaimed by filtering, centrifuging and/or be decanted Solid 3,5- bis- substitute -1,2,4- oxadiazole products.

3,5- bis- substitute -1,2,4- oxadiazole products to be constantly precipitated as fine crystal solid, and may The solid of pearl (such as several millimeters of diameter), irregular big lump or concrete mulching can be formed on reactor wall and agitator, This is for being a problem from reactor discharge and following process.A solution is not remove by-product salt aqueous phase.However, 3,5- bis- substitute high residual salt (such as NaCl) level in -1,2,4- oxadiazole products to cause to ask in product preparation Topic.

It using surfactant so that product (is probably meta-stable melt or highly dense that one alternate embodiment, which is, Contracting solution) droplets stable, and cause drop to be solidified as sediment in water layer without gathering into larger drop, it is described compared with Otherwise big drop may finally " knocking-on " be the solid of bulk and/or concrete mulching.Suitable surfactant can be selected from The group consisted of：Anion or non-ionic dispersing agent, anion or nonionic detergent, anion or non-ionic surface are lived Property agent and its combination.The non-limiting examples of suitable surfactant include Morwet D-425 (anionic dispersing agents, alkyl Naphthalene sulphonate condensation sodium salt, from Akzo Nobel), Morwet D-425 and Greenworks (NaLS (anion Cleaning agent), alkyl poly glucoside (nonionic surfactant), lauryl amine oxide (nonionic detergent) and glycerine), Morwet D-425 and Pluronic L-35 (surfactant, the PEG-PPG- of polyethylene glycol propane diols-polyethylene glycol PEG block copolymer, Mn ≈ 1900), Pluronic L-35 and Triton X-100 (nonionic detergent, octyl phenol second Epoxide compound (n ≈ 10)).In one embodiment, removed after reaction essentially completes and from reactant mixture Before at least a portion organic solvent not miscible with water, addition surfactant is into reactant mixture.

In some embodiments, can be with specifically in the large-scale methods or manufacturing environment with a large amount of solvents By solvent recovery and recycle to be used further in method (such as dissolving N- hydroxyamidines in being circulated in subsequent processes).

It is as described above to be used to preparing 3,5- bis- and substitute the formula (IIa) of -1,2,4- oxadiazoles or the N- hydroxyamidines of (IIb) With obtained from commercial source, or can be prepared using method known to those skilled in the art.For example, aryl amide oxime (such as benzoyl amidoxime) or optionally independently substituted aryl amide oxime can be by making corresponding aryl nitrile and hydroxylamine salt Hydrochlorate and aqueous alkali are reacted to prepare.A kind of exemplary aqueous alkali for this purpose is sodium hydroxide.

In some cases, to prepare aryl amide oxime initial substance, make hydroxylamine hydrochloride alcoholic solvent (such as methanol or Ethanol) in combined into slurry, and by it with the aqueous alkali of equimolar amounts.In one embodiment, to cause azanol mistake The amount of amount, e.g., from about 1.01 to about 1.25 molar equivalents addition aryl nitrile.Gained reaction is gentle heat release, and gained is anti- Mixture is answered to be heated to about 20 DEG C to about 75 DEG C, about 20 DEG C to about 65 DEG C, about 50 DEG C to about 75 DEG C or about 50 DEG C to about 60 DEG C Temperature.With heating response mixture, aryl nitrile is added.Then in some embodiments, reactant mixture is made to continue to heat Until reaction is completed.

After completion of reaction, aryl amide oxime product can be separated for disclosed method.For example, can be with Alcoholic solvent is removed by distilling, leaves the reactant mixture comprising product melt phase and aqueous phase.It is still hot in reactant mixture When, organic solvent as described above is added so that aryl amide oxime product is dissolved in organic phase.Then can separate and Remove aqueous phase.In various embodiments, organic solvent is met substitutes the organic of -1,2,4- oxadiazoles for manufacturing 3,5- bis- The criterion that solvent is elaborated as more than.Therefore, the organic solvent of the aryl amide oxime product comprising dissolving can be made mutually to exist Substitute -1,2,4- oxadiazoles without condensation/cyclization is entered directly into the case of being processed further to manufacture 3,5- bis-.This Method described in text can be easily adapted to manufacture other formulas (IIa) or the N- hydroxyl amidine compounds of (IIb).

In an alternate embodiment, aryl amide oxime initial substance (such as benzoyl amidoxime) is by making corresponding virtue Base nitrile and aqueous hydroxylamine solution (such as aqueous hydroxylamine solution includes but is not limited to the hydroxylamine free acid aqueous solution or as caused by hydrochloride Aqueous hydroxylamine solution) combine and react to prepare.By using aqueous hydroxylamine solution, reacted with aqueous alkali with hydroxylamine hydrochloride The step of thing, is eliminated together with the demand to alcoholic solvent.This due in the absence of aqueous alkali, alcohol storage and distillation equipment with And other advantages (such as simplifying the processing of waste water by avoiding producing salt in neutralization procedure) and extensive Notable capital and material economy are provided in manufacture method.Aryl amide oxime initial substance is made using aqueous hydroxylamine solution wherein In a standby embodiment, it is not necessary to solvent.However, it is possible to use solvent, including alcoholic solvent, such as methanol or ethanol.For Contribute to following process, solvent for use can be not miscible with water organic solvent or solvent combination, based on more than such as in detail One or more of criterion carefully illustrated is selected.For example, organic solvent can be butyl acetate or 2- methyl four Hydrogen furans.Or if aryl amide oxime initial substance by making corresponding aryl nitrile and aqueous hydroxylamine solution in the absence of solvent Combine and react to prepare, then after the reaction was completed, products therefrom can be dissolved in organic solvent as described above In to be processed further.

It is as described above to be used to manufacturing 3,5- bis- and substitute formula (IIIa) in the method for -1,2,4- oxadiazoles or (IIIb) Acyl chlorides (such as 2 thiophen carbonyl chloride or 2- furans phosgene) can be obtained from commercial source, or can use those skilled in the art It is prepared by known method.For example, 2- acetyl thiophenes or 2 thiophene carboxaldehyde can be manufactured using thiophene.It can use Each of which person manufactures 2- thiophenic acids and subsequent 2 thiophen carbonyl chloride.Other methods can be suitably used to manufacture formula (III) other chloride compounds or in the range of (IIIb).

Following examples should be regarded as only having illustrative, and be not intended to limit the scope of the present disclosure.

Embodiment

Embodiment 1：Prepare benzoyl amidoxime

By in hydroxylamine hydrochloride (8.85g, 0.126 mole) and methanol (45mL) feed-in 100mL flasks, 51% is later fed into Sodium hydroxide (9.82g, 0.125 mole).Benzonitrile (10.32g, 0.100 mole) is added into this mixture, and will reaction Thing is heated to 55-60 DEG C, and is kept for 2 hours.HPLC shows that benzonitrile disappears, and reaction is completed.A part is removed by distilling Methanol (30mL), deionization (DI) water (22mL) is added, and remaining methanol is distilled to obtain two liquid phase (benzene under 300 supports Formyl amidoxime melt and salt solution).2- methyltetrahydrofurans (20.0g) are added, and drain aqueous salt phase to obtain 33.34g Solution of the benzoyl amidoxime in 2- methyltetrahydrofurans, be 39.45% by drying loss and HPLC.Benzoyl amidoxime Yield is 96.5%.

Embodiment 2：3- phenyl-the 5- (thiophene -2- bases) -1 being prepared in 2- methyl-tetrahydro furans, 2,4- oxadiazoles

By in 39.45% solution (33.34g) the feed-in 100mL flasks of benzoyl amidoxime in 2- methyltetrahydrofurans, with (3.52g, 0.045 rubs for feed-in water (9.0g), 40% aqueous solution (1.02g) of TBAH and 51% sodium hydroxide afterwards You).Into this mixture 2 thiophen carbonyl chloride (13.83g, 0.0936 mole) and 51% hydrogen-oxygen are added through 30 minutes simultaneously Change sodium (7.33g, 0.0935 mole) while heated to about 70 DEG C.Reaction is completed in less than 80 minutes.Aqueous salt phase is removed, is added Add water (30g), and 2- methyltetrahydrofurans (13.5mL) are removed by air-distillation part.Add the heat of additional quantity (32g) Water, and remaining 2- methyltetrahydrofurans are distilled out, during the time, product 3- phenyl -5- (2- thienyls) -1, 2,4- oxadiazoles precipitate.By 3- phenyl -5- (2- thienyls) -1, the aqueous slurry solution of 2,4- oxadiazoles is filtered, is washed with water, and And be dried overnight in vacuum drying oven, to produce 3- phenyl -5- (2- thienyls) -1,2,4- oxadiazoles, 20.47g, 99.1% It is pure, 95.0% yield.

Embodiment 3：3- phenyl-the 5- (thiophene -2- bases) -1 being prepared in acetone, 2,4- oxadiazoles

Benzoyl amidoxime (5.00g, 36.7mmol) is dissolved at 0 DEG C in acetone (50mL).Agitating solution, and add Add 50% sodium hydrate aqueous solution (4.5mL).Heat release is noticed, and forms sediment in the reactive mixture.Heat release continues About 15 minutes, and slurry retrogradation.Solution is warming up to 20 DEG C, and add outside cooling.Through 15 minutes addition 2- thiophene carbon Acyl chlorides (5.36g, 36.7mmol), maintenance reaction mixture are less than 30 DEG C.Reaction is maintained at 30 DEG C 15 minutes, and slurry It is thinning.Reactant mixture is cooled to room temperature, and be stirred for 20 minutes.Water (50mL) is added, and it is small to stir gained solid 1 When.Solid is collected by vacuum filter, washed with water (2 × 50mL), and at Buchner funnel (Buchner funnel) On under a gas flow from being dried in vacuum overnight.Obtain the 3- phenyl -5- (2- thienyls) -1 of white solid-like, 2,4- oxadiazoles (6.94g, 30.4mmol) (83% yield).

Embodiment 4：Prepare benzoyl amidoxime

By in hydroxylamine hydrochloride (88.5g, 1.26 moles) and methanol (450mL) feed-in 1000mL flasks, it is later fed into 51% sodium hydroxide (97.7g, 1.25 moles).Benzonitrile (103.1g, 1.00 moles) is added, and reactant is heated to Continue 4 hours after 65-71 DEG C.HPLC shows that benzonitrile disappears, and reaction is completed.A part of methanol is removed by distilling (366mL), addition DI water (200mL), and under 200 supports distill remaining methanol (benzoyl amidoxime melts to obtain two liquid phases Compound and salt solution).Butyl acetate (650mL) and DI water (100mL) are added, and drains aqueous salt phase.By butyl acetate solution With 100mL water washings once, to obtain blue turbid solution of the 715.04g benzoyl amidoxime in butyl acetate, by dry Dry loss is 18.1%.The yield of benzoyl amidoxime is 95.1%, and benzamide accessory substance is 3.4% yield.

Embodiment 5：Prepare benzoyl amidoxime

Benzonitrile (25.0g, 242mmol) is added in 250mL flasks, and is heated to 50 DEG C.Via injection Device pump is with 0.17mL/min (2 hours addition time) addition aqueous hydroxylamine solution (50%, 20.4g, 309mmol).Complete to add After 50% aqueous hydroxylamine solution, reactant 1 hour is stirred at 50 DEG C 30 minutes.Reaction is completed, and adds 80mL 2- methyl Tetrahydrofuran and 25mL water.Solution is mixed 10 minutes, and separates each layer.Collect water white organic layer (96.3g).Analyzing When, organic layer contains 29.48w/w% benzoyl amidoxime product (28.4g, 208mmol).Yield is 86%.

Embodiment 6：Prepare benzoyl amidoxime

Benzonitrile (50.0g, 0.485mol) is added in 250mL flasks, and is heated to 70 DEG C under agitation. Deionized water (1.0g) is added, and is kept the temperature at 70 DEG C.Via syringe pump through 1.5 hours addition aqueous hydroxylamine solutions (50%, 37.50g, 34.8ml, analysis are 53.3%, 0.605 mole), while temperature is maintained at 70 DEG C ± 2 DEG C.HPLC points Analysis shows, after the reaction time of about 2.5 hours, the conversion of benzonitrile is ＞ 99%.The batch is heated at 70 DEG C 3.5 hours altogether, then it is cooled to 60 DEG C.The batch is transferred to the 500mL with 2- methyltetrahydrofurans (208.98g) In flask, the 20 weight %NaCl aqueous solution (40.0g) are then added.60 DEG C are heated the mixture to, and is separated at 60 DEG C Each phase, to obtain solution (281.80g) and waste water (44.61g) of the benzoyl amidoxime in 2- methyltetrahydrofurans. The liquor analysis of 2- methyltetrahydrofurans is 21.73 weight % benzoyl amidoximes.

Embodiment 7：3- phenyl-the 5- (thiophene -2- bases) -1 being prepared in butyl acetate, 2,4- oxadiazoles

By solution (27.30g, 36.7mmol) the feed-in 100mL flasks of benzoyl amidoxime (18.3%) in butyl acetate In, it is later fed into the 40% TBAH aqueous solution (0.40g) and 51% sodium hydroxide (0.86g, 11.0mmol).To this In mixture through add simultaneously within 30 minutes 2 thiophen carbonyl chloride (5.44g, 36.8mmol) and 51% sodium hydroxide (2.88g, 36.7mmol), while heated to about 70 DEG C.The extra sodium hydroxides of 0.66g 51% are added so that pH is increased into 9.75.Reaction exists (HPLC analyses) is completed in less than 2.5 hours.Hot deionized water (10mL) is added with dissolving salt, is subsequently isolated, with 10mL hot water Washing, and separate.Add deionized water (50mL), and by under 66-75 DEG C and 300 supports azeotropic distillation remove acetic acid Butyl ester.3- phenyl -5- (thiophene -2- bases) -1,2,4- oxadiazoles precipitate during distillation.Product is discharged, passes through coarse glass frit Filtering, is washed with water (2 × 15mL), and is dried overnight in vacuum drying oven, to obtain 3- phenyl -5- (thiophene -2- bases) -1, 2,4- oxadiazoles (7.50g, 88.2%)；98.6% purity.

Embodiment 8：Prepare 4- chlorobenzoyl amidoximes

50% sodium hydrate aqueous solution (2.8g, 36.34mmol) is mixed in methanol (20.0mL).Add azanol hydrochloric acid Salt (2.55g, 36.34mmol), and stir mixture 5 minutes.4- chlorobenzonitriles (4.0g, 29.08mmol) are added, and will Mixture is heated to 60 DEG C.Heterogeneous mixture is stirred at 60 DEG C 3 hours.Mixture is poured into water (30mL), solid Dissolve and sediment occur.Methanol is removed under reduced pressure, and remaining solid is collected by vacuum filter.By solid water (2 × 10mL) is washed.Obtain the 4- chlorobenzoyls amidoxime (4.38g, 25.6mmol) (88% yield) of white solid-like.

Embodiment 9：Prepare 3- (4- chlorphenyls) -5- (2- thienyls) -1,2,4- oxadiazoles

4- chlorobenzoyls amidoxime (1.00g, 5.8mmol) is dissolved in 2- methyltetrahydrofurans (10.0mL) and water In (1.0mL).The 40% benzyl trimethylammonium hydroxide aqueous solution (100 μ L) is added, and solution is heated to 50 DEG C.Through 15 Minute be added dropwise simultaneously 50% sodium hydrate aqueous solution (720mg, 9.00mmol) and 2 thiophen carbonyl chloride (939.0mg, 6.4mmol).The temperature of mixture is warming up to 70 DEG C.Mixture is cooled to room temperature, and adds water (40mL).Form solid, And 2- methyltetrahydrofurans are removed under reduced pressure.Solid is separated by vacuum filter.Obtain the 3- (4- of white solid-like Chlorphenyl) -5- (2- thienyls) -1,2,4- oxadiazoles (1.32g, 5.0mmol) (86% yield).

Embodiment 10：Prepare 3- (4- chlorphenyls) -5- (2- furyls) -1,2,4- oxadiazoles

4- chlorobenzoyls amidoxime (1.24g, 7.25mmol) is dissolved in 2- methyltetrahydrofurans (10.0mL) and water In (1.0mL).Add the 40% benzyl trimethylammonium hydroxide aqueous solution (100 μ L) and 50% sodium hydrate aqueous solution (736mg, 9.20mmol).Mixture is stirred, and forms sediment.Furans acyl chlorides (1.24g, 7.25mmol) is added dropwise, And notice heat release.Mixture is stirred 1 hour at 70 DEG C, and is cooled to room temperature.Solution is poured into water (25mL) In, and 2- methyltetrahydrofurans are removed under reduced pressure.By vacuum filter come separating obtained solid.Obtain white solid-like 3- (4- chlorphenyls) -5- (2- furyls) -1,2,4- oxadiazoles (1.22g, 4.94mmol) (68% yield).

Embodiment 11：Prepare 3- phenyl -5- (2- furyls) -1,2,4- oxadiazoles

By benzoyl amidoxime (2.00g, 14.7mmol) and the 40% benzyl trimethylammonium hydroxide aqueous solution (100 μ L) group Together in 2- methyltetrahydrofurans (20mL) and water (2mL).Solution is warming up to 50 DEG C, 50% was added dropwise simultaneously through 10 minutes Sodium hydrate aqueous solution (1.52g, 19.1mmol) and 2- furans acyl chlorides (2.00g, 15.3mmol).Pot temperature is increased to 74 DEG C. Mixture is stirred at 60 DEG C 48 hours, and solid dissolving.Mixture is cooled to room temperature, and is poured into water (25mL) In.2- methyltetrahydrofurans are removed under reduced pressure, and form solid in aqueous.Solid is collected by vacuum filter. Obtain the 3- phenyl -5- (2- furyls) -1 of white solid-like, 2,4- oxadiazoles (2.33g, 9.5mmol) (64% yield).

Embodiment 12：Prepare 3- phenyl -5- (thiophene -2- bases) -1,2,4- oxadiazoles

Solution feed-in 500mL of the benzoyl amidoxime (24.92%) in 2- methyl THF (67.53g, 124 mMs) is burnt In bottle, be later fed into DI water (20.0g), the 55% TBAH aqueous solution (0.94g) and 50% sodium hydroxide (0.96g, 12 mMs).Into this mixture 2 thiophen carbonyl chloride (17.77g, 120 mMs) and 50% hydrogen were added through 30 minutes simultaneously Sodium oxide molybdena (9.60g, 120 mMs), while heated to about 70 DEG C.Reaction is completed in less than one hour.Reduce the temperature to 60 DEG C, and the pH of aqueous phase is neutralized to 7.61, and drain discarded object.1.25g Morwet D-425 are added in 100ml DI Hot solution in water heats 2 phase mixtures to distill out 2- methyltetrahydrofurans/water azeotropic mixture (boiling point into mixture 71℃).After 2- methyltetrahydrofurans start to distill out, additional water (150mL) was aspirated into reactor flask through about 15 minutes. Well-stirred simultaneously in maintenance, pot temperature reaches 100.5 DEG C (97 DEG C of steam temperatures).Slurry is cooled down, and uses thick glass Glass powder filters.Merge by incrustation under stirrer scraping and with wet cake；Incrustation is only about the 3% of gross product.By through merging Wet cake is washed with hot DI water (3 × 50ml), and is sucked and dried 5 minutes, to obtain 3- phenyl -5- (thiophene -2- bases) -1,2, 4- oxadiazole wet cakes, 34.80g.The drying loss of wet cake is 20.13%.Through dry 3- phenyl -5- (thiophene -2- bases) - The analysis of 1,2,4- oxadiazole is 96.12%, and residual chloride is ＜ 200ppm.

Embodiment

In order to further illustrate, other non-limiting embodiments of the disclosure are set forth below.

For example, embodiment 1 is that a kind of 3, the 5- bis- of formula (Ia) substitutes 1,2,4- oxadiazoles or the side of its salt Method,

Methods described is following including making：Any one in the N- hydroxyamidines of formula (IIa) or its possible tautomeric form,

With the acyl chlorides of formula (IIIa),

Reacted in the reactant mixture comprising organic solvent and aqueous alkali not miscible with water, wherein described The temperature of reactant mixture is no more than about 85 DEG C；

And wherein Ar¹It is phenyl, pyridine radicals, pyrazolyl, oxazolyl Huo isoxazolyls, it each can be optionally independent Ground is substituted by one or more substituents, and the substituent is selected from the group consisted of：Halogen, CF₃、CH₃、OCF₃、OCH₃、 CN and C (H) O；And

Ar²It is thienyl, furyl, oxazolyl Huo isoxazolyls, it each can be optionally independently by one or more Individual substituent substitution, the substituent are selected from the group consisted of：Fluorine, chlorine, CH₃And OCF₃。

Embodiment 2 is the method according to embodiment 1, wherein the reactant mixture further includes phase transfer Catalyst.

Embodiment 3 is the method according to embodiment 2, is consisted of wherein the phase transfer catalyst is selected from Group：Quaternary ammonium salt, phosphonium salts and crown ether.

Embodiment 4 is the method according to embodiment 2 or 3, wherein the phase transfer catalyst is selected from by following The group of composition：TBAH, TBAB, tetrabutyl ammonium fluoride, tetrabutylammonium iodide, Si butyl phosphonium bromide, 4-butyl phosphonium chloride and benzyl trimethylammonium hydroxide.

Embodiment 5 is the method according to embodiment 4, wherein the phase transfer catalyst is tetrabutylammonium hydroxide Ammonium.

Embodiment 6 is the method according to any one of embodiment 1 to 5, wherein described can not be miscible with water Organic solvent makes the N- hydroxyamidines of the formula (IIa) and 3, the 5- bis- of the formula (Ia) substitute -1,2,4- oxadiazoles to dissolve.

Embodiment 7 is the method according to any one of embodiment 1 to 6, wherein described can not be miscible with water Organic solvent forms azeotropic mixture with water.

Embodiment 8 is the method according to any one of embodiment 1 to 7, wherein described can not be miscible with water Organic solvent is selected from the group consisted of：2- methyltetrahydrofurans and butyl acetate.

Embodiment 9 is the method according to embodiment 8, wherein it is described can not organic solvent miscible with water be 2- Methyltetrahydrofuran.

Embodiment 10 is the method according to any one of embodiment 1 to 9, wherein the aqueous alkali be selected from by Group consisting of：Sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide.

Embodiment 11 is the method according to embodiment 10, wherein the aqueous alkali is selected from what is consisted of Group：Sodium hydroxide and potassium hydroxide.

Embodiment 12 is the method according to any one of embodiment 1 to 11, wherein the reactant mixture bag Containing organic phase and aqueous phase.

Embodiment 13 is the method according to embodiment 12, wherein the pH of the aqueous phase is greater than about 8.

Embodiment 14 is the method according to embodiment 12, wherein the pH of the aqueous phase is greater than about 10.

Embodiment 15 is the method according to any one of embodiment 12 to 14, wherein by adding extra buck Solution increases or maintained the pH of the aqueous phase into the reactant mixture.

Embodiment 16 is the method according to any one of embodiment 1 to 15, wherein by the reactant mixture Temperature maintain at about 55 DEG C to about 75 DEG C.

Embodiment 17 is the method according to any one of embodiment 1 to 15, wherein making the formula (IIa) N- Hydroxyamidines is dissolved in the organic solvent not miscible with water, and the acyl chlorides for then adding the formula (IIIa) is described to be formed Reactant mixture.

Embodiment 18 is the method according to any one of embodiment 1 to 17, and it further comprises from described After reactant mixture removes organic solvent not miscible with water described at least a portion, with the precipitated form from water layer 3, the 5- bis- that the formula (Ia) is reclaimed from the reactant mixture substitutes -1,2,4- oxadiazoles.

Embodiment 19 is the method according to embodiment 18, and it further comprises adding surfactant described in In reactant mixture.

Embodiment 20 is the method according to embodiment 19, wherein being added to described in the reactant mixture Surfactant makes 3, the 5- bis- of the formula (Ia) substitute the drop of -1,2,4- oxadiazoles to be dissolved in water layer and caused described Drop solidifiable is without being agglomerated into larger drop.

Embodiment 21 is the method according to embodiment 19 or 20, wherein from the reactant mixture remove to Before organic solvent not miscible with water described in a few part, the surfactant is added into the reactant mixture.

Embodiment 22 is the method according to any one of embodiment 19 to 21, wherein substantial in the reaction After completion, the surfactant is added into the reactant mixture.

Embodiment 23 is the method according to any one of embodiment 19 to 22, wherein the surfactant selects Free group consisting of：Anion or non-ionic dispersing agent, anion or nonionic detergent, anion or non-ionic surface Activating agent and its combination.

Embodiment 24 is the method according to any one of embodiment 1 to 23, wherein the N- hydroxyls of the formula (IIa) Base amidine and oxime ester intermediate, its salt or its tautomerism shape of the reacting generating (IVa) of the acyl chlorides of the formula (IIIa) Formula,

Wherein Ar¹And Ar²As defined in embodiment 1.

Embodiment 25 is the method according to embodiment 24, wherein it is described can not organic solvent miscible with water make 3, the 5- bis- of the N- hydroxyamidines of the formula (IIa), the oxime ester intermediate of the formula (IVa) and the formula (Ia) substitutes 1,2,4- Evil Diazole dissolves.

Embodiment 26 is the method according to embodiment 24 or 25, wherein in separating the oxime ester of the formula (IVa) Mesosome, 3, the 5- bis- for subsequently forming the formula (Ia) substitute 1,2,4- oxadiazoles.

Embodiment 27 is the method according to any one of embodiment 1 to 26, wherein the N- hydroxyls of the formula (IIa) Base amidine is to be carried out by making substituted or unsubstituted benzonitrile with hydroxylamine hydrochloride in the alcoholic solvent with sodium hydroxide The benzoyl amidoxime for reacting and being formed, and the benzoyl amidoxime is separated from the alcoholic solvent, and then it is dissolved in choosing In the solvent of free group consisting of：2- methyltetrahydrofurans and butyl acetate.

Embodiment 28 is the method according to any one of embodiment 1 to 26, wherein the N- hydroxyls of the formula (IIa) Base amidine is the benzoyl amidoxime by forming substituted or unsubstituted benzonitrile and azanol reaction, and makes to be formed Benzoyl amidoxime be dissolved in the solvent selected from the group consisted of：2- methyltetrahydrofurans and butyl acetate.

Embodiment 29 is the method according to embodiment 27 or 28, wherein to form the formula (IIa) benzene The reaction of formyl amidoxime is carried out at a temperature of about 20 DEG C to about 75 DEG C.

Embodiment 30 is the method according to any one of embodiment 1 to 26, wherein the N- hydroxyls of the formula (IIa) Base amidine is by making substituted or unsubstituted benzonitrile be combined with aqueous hydroxylamine solution and reacting the benzamide to be formed Oxime.

Embodiment 31 is the method according to embodiment 30, wherein the substituted or unsubstituted benzonitrile Merging and reacting in the absence of organic solvent the following group not miscible with water with aqueous hydroxylamine solution.

Embodiment 32 is the method according to embodiment 30, wherein the substituted or unsubstituted benzonitrile Combine and react in organic solvent not miscible with water with aqueous hydroxylamine solution, and the benzoyl amidoxime is dissolved in institute State in solvent.

Embodiment 33 is the method according to embodiment 32, wherein the organic solvent choosing that can not be miscible with water Free group consisting of：2- methyltetrahydrofurans and butyl acetate.

Embodiment 34 is the method according to any one of embodiment 1 to 33, and wherein methods described includes：

(1) solution by the N- hydroxyamidines of the formula (IIa) to be dissolved in the organic solvent not miscible with water Form is incorporated into reaction vessel；

(2) a part of aqueous alkali and optionally phase transfer catalyst are added into the reaction vessel；

(3) acyl chlorides of the formula (IIIa) is added into the reaction vessel to form the reactant mixture；With

(4) extra aqueous alkali is added into the reactant mixture in the reaction vessel.

Embodiment 35 is the method according to embodiment 34, wherein the organic solvent choosing that can not be miscible with water Free group consisting of：2- methyltetrahydrofurans and butyl acetate.

Embodiment 36 is the method according to embodiment 34 or 35, wherein adding the acyl chlorides and the volume simultaneously Outer aqueous alkali is into the reaction vessel.

Embodiment 37 is the method according to embodiment 34 or 35, wherein sequentially adding the acyl chlorides and the volume Outer aqueous alkali is into the reaction vessel.

Embodiment 38 is the method according to any one of embodiment 1 to 37, wherein Ar¹It is unsubstituted benzene Base.

Embodiment 39 is the method according to any one of embodiment 1 to 37, wherein Ar¹It is the benzene being mono-substituted Base, wherein the substituent is halogen.

Embodiment 40 is the method according to any one of embodiment 1 to 37, wherein Ar¹It is by dibasic chlorine Alkyl phenyl.

Embodiment 41 is the method according to any one of embodiment 1 to 40, wherein Ar²Substituted or not by Substituted thiophene or furans.

Embodiment 42 is the method according to embodiment 41, wherein Ar²It is unsubstituted thiophene.

Embodiment 43 is the method according to any one of embodiment 1 to 37, wherein the 3,5- of the formula (Ia) Two -1,2,4- oxadiazoles of substitution are 3- phenyl -5- (2- thienyls) -1,2,4- oxadiazoles.

Embodiment 44 is the method according to any one of embodiment 1 to 37, wherein the 3,5- of the formula (Ia) Two -1,2,4- oxadiazoles of substitution are 3- (4- chlorphenyls) -5- (2- furyls) -1,2,4- oxadiazoles.

Embodiment 45 is the method according to any one of embodiment 1 to 37, wherein the 3,5- of the formula (Ia) Two -1,2,4- oxadiazoles of substitution are 3- (4- chloro-2-methyls phenyl) -5- (2- furyls) -1,2,4- oxadiazoles.

Embodiment 46 is the method according to any one of embodiment 1 to 37, wherein the 3,5- of the formula (Ia) Two -1,2,4- oxadiazoles of substitution are 3- phenyl -5- (2- furyls) -1,2,4- oxadiazoles.

Embodiment 47 is that a kind of 3, the 5- bis- of formula (Ib) substitutes 1,2,4- oxadiazoles or the method for its salt,

Methods described is following including making：Any one in the N- hydroxyamidines of formula (IIb) or its possible tautomeric form,

With the acyl chlorides of formula (IIIb),

Embodiment 48 is the method according to embodiment 47, wherein the reactant mixture further turns comprising phase Shifting catalyst.

Embodiment 49 is the method according to embodiment 48, wherein the phase transfer catalyst is selected from by with the following group Into group：Quaternary ammonium salt, phosphonium salts and crown ether.

Embodiment 50 is the method according to embodiment 48 or 49, wherein the phase transfer catalyst be selected from by with The group of lower composition：TBAH, TBAB, tetrabutyl ammonium fluoride, tetrabutylammonium iodide, tetrabutyl phosphonium bromide Phosphonium, 4-butyl phosphonium chloride and benzyl trimethylammonium hydroxide.

Embodiment 51 is the method according to embodiment 50, wherein the phase transfer catalyst is tetrabutyl hydrogen-oxygen Change ammonium.

Embodiment 52 is the method according to any one of embodiment 47 to 51, wherein described can not be miscible with water Organic solvent make the N- hydroxyamidines of the formula (IIb) and 3, the 5- bis- of the formula (Ib) substitutes -1,2,4- oxadiazoles to dissolve.

Embodiment 53 is the method according to any one of embodiment 47 to 52, wherein described can not be miscible with water Organic solvent and water form azeotropic mixture.

Embodiment 54 is the method according to any one of embodiment 47 to 53, wherein described can not be miscible with water Organic solvent be selected from the group that consists of：2- methyltetrahydrofurans and butyl acetate.

Embodiment 55 is the method according to embodiment 54, wherein it is described can not organic solvent miscible with water be 2- methyltetrahydrofurans.

Embodiment 56 is the method according to any one of embodiment 47 to 55, wherein the aqueous alkali is selected from The group consisted of：Sodium hydroxide, potassium hydroxide, lithium hydroxide and calcium hydroxide.

Embodiment 57 is the method according to embodiment 56, wherein the aqueous alkali is selected from what is consisted of Group：Sodium hydroxide and potassium hydroxide.

Embodiment 58 is the method according to any one of embodiment 47 to 57, wherein the reactant mixture bag Containing organic phase and aqueous phase.

Embodiment 59 is the method according to embodiment 58, wherein the pH of the aqueous phase is greater than about 8.

Embodiment 60 is the method according to embodiment 58, wherein the pH of the aqueous phase is greater than about 10.

Embodiment 61 is the method according to any one of embodiment 58 to 60, wherein by adding extra buck Solution increases or maintained the pH of the aqueous phase into the reactant mixture.

Embodiment 62 is the method according to any one of embodiment 47 to 61, wherein by the reactant mixture Temperature maintain at about 55 DEG C to about 75 DEG C.

Embodiment 63 is the method according to any one of embodiment 47 to 62, wherein making the formula (IIb) N- hydroxyamidines is dissolved in the organic solvent not miscible with water, then adds the acyl chlorides of the formula (IIIb) to be formed State reactant mixture.

Embodiment 64 is the method according to any one of embodiment 47 to 63, and it further comprises from described After reactant mixture removes organic solvent not miscible with water described at least a portion, with the precipitated form from water layer 3, the 5- bis- that the formula (Ib) is reclaimed from the reactant mixture substitutes -1,2,4- oxadiazoles.

Embodiment 65 is the method according to embodiment 64, and it further comprises adding surfactant described in In reactant mixture.

Embodiment 66 is the method according to embodiment 65, wherein being added to described in the reactant mixture Surfactant makes 3, the 5- bis- of the formula (Ib) substitute the drop of -1,2,4- oxadiazoles to be dissolved in water layer and caused described Drop solidifiable is without being agglomerated into larger drop.

Embodiment 67 is the method according to embodiment 65 or 66, wherein from the reactant mixture remove to Before organic solvent not miscible with water described in a few part, the surfactant is added into the reactant mixture.

Embodiment 68 is the method according to any one of embodiment 65 to 67, wherein substantial in the reaction After completion, the surfactant is added into the reactant mixture.

Embodiment 69 is the method according to any one of embodiment 65 to 68, wherein the surfactant selects Free group consisting of：Anion or non-ionic dispersing agent, anion or nonionic detergent, anion or non-ionic surface Activating agent and its combination.

Embodiment 70 is the method according to any one of embodiment 47 to 69, wherein the N- of the formula (IIb) Oxime ester intermediate, its salt or its tautomerism of hydroxyamidines and the reacting generating (IVb) of the acyl chlorides of the formula (IIIb) Form,

Wherein Ar¹And Ar²As defined in embodiment 47.

Embodiment 71 is the method according to embodiment 70, wherein it is described can not organic solvent miscible with water make 3, the 5- bis- of the N- hydroxyamidines of the formula (IIb), the oxime ester intermediate of the formula (IVb) and the formula (Ib) substitutes 1,2,4- Evil Diazole dissolves.

Embodiment 72 is the method according to embodiment 70 or 71, wherein in separating the oxime ester of the formula (IVb) Mesosome, 3, the 5- bis- for subsequently forming the formula (Ib) substitute 1,2,4- oxadiazoles.

Embodiment 73 is the method according to any one of embodiment 47 to 72, wherein the N- of the formula (IIb) Hydroxyamidines is to be entered by making substituted or unsubstituted benzonitrile with hydroxylamine hydrochloride in the alcoholic solvent with sodium hydroxide The benzoyl amidoxime that row reacts and formed, and the benzoyl amidoxime is separated from the alcoholic solvent, and be then dissolved in In solvent selected from the group consisted of：2- methyltetrahydrofurans and butyl acetate.

Embodiment 74 is the method according to any one of embodiment 47 to 72, wherein the N- of the formula (IIb) Hydroxyamidines is the benzoyl amidoxime by forming substituted or unsubstituted benzonitrile and azanol reaction, and makes institute's shape Into benzoyl amidoxime be dissolved in the solvent selected from the group consisted of：2- methyltetrahydrofurans and butyl acetate.

Embodiment 75 is the method according to embodiment 73 or 74, wherein to form the formula (IIb) benzene The reaction of formyl amidoxime is carried out at a temperature of about 20 DEG C to about 75 DEG C.

Embodiment 76 is the method according to any one of embodiment 47 to 72, wherein the N- of the formula (IIb) Hydroxyamidines is by making substituted or unsubstituted benzonitrile be combined with aqueous hydroxylamine solution and reacting the benzoyl to be formed Amidoxime.

Embodiment 77 is the method according to embodiment 76, wherein the substituted or unsubstituted benzonitrile Merging and reacting in the absence of organic solvent the following group not miscible with water with aqueous hydroxylamine solution.

Embodiment 78 is the method according to embodiment 76, wherein the substituted or unsubstituted benzonitrile Combine and react in organic solvent not miscible with water with aqueous hydroxylamine solution, and the benzoyl amidoxime is dissolved in institute State in solvent.

Embodiment 79 is the method according to embodiment 78, wherein the organic solvent choosing that can not be miscible with water Free group consisting of：2- methyltetrahydrofurans and butyl acetate.

Embodiment 80 is the method according to any one of embodiment 47 to 79, and wherein methods described includes：

(1) solution by the N- hydroxyamidines of the formula (IIb) to be dissolved in the organic solvent not miscible with water Form is incorporated into reaction vessel；

(3) acyl chlorides of the formula (IIIb) is added into the reaction vessel to form the reactant mixture；With

Embodiment 81 is the method according to embodiment 80, wherein the organic solvent choosing that can not be miscible with water Free group consisting of：2- methyltetrahydrofurans and butyl acetate.

Embodiment 82 is the method according to embodiment 80 or 81, wherein adding the acyl chlorides and the volume simultaneously Outer aqueous alkali is into the reaction vessel.

Embodiment 83 is the method according to embodiment 80 or 81, wherein sequentially adding the acyl chlorides and the volume Outer aqueous alkali is into the reaction vessel.

Embodiment 84 is the method according to any one of embodiment 47 to 83, wherein Ar¹It is unsubstituted Phenyl.

Embodiment 85 is the method according to any one of embodiment 47 to 83, wherein Ar¹It is mono-substituted Phenyl, wherein the substituent is halogen.

Embodiment 86 is the method according to any one of embodiment 47 to 83, wherein Ar¹It is dibasic Chlorine alkyl phenyl.

Embodiment 87 is the method according to any one of embodiment 47 to 86, wherein Ar²It is substituted or not Substituted thiophene or furans.

Embodiment 88 is the method according to embodiment 87, wherein Ar²It is unsubstituted thiophene.

Embodiment 89 is the method according to any one of embodiment 47 to 83, wherein the 3,5- of the formula (Ib) Two -1,2,4- oxadiazoles of substitution are 3- (thiophene -2- bases) -5- (p-methylphenyl) -1,2,4- oxadiazoles.

Embodiment 90 is the method according to any one of embodiment 47 to 83, wherein the 3,5- of the formula (Ib) Two -1,2,4- oxadiazoles of substitution are 5- (3- chlorphenyls) -3- (thiophene -2- bases) -1,2,4- oxadiazoles.

Embodiment 91 is the method according to any one of embodiment 47 to 83, wherein the 3,5- of the formula (Ib) Two -1,2,4- oxadiazoles of substitution are 5- (4- chloro-2-methyls phenyl) -3- (furans -2- bases) -1,2,4- oxadiazoles.

Embodiment 92 is the method according to embodiment 27 or 73, wherein the alcoholic solvent is methanol.

When the key element for introducing the disclosure or its preferred embodiment, article " one (a) ", " one (an) ", " described (the) " and " (said) " is intended to mean one or more of described key element be present.Term "comprising", " comprising " and " tool Have " be intended to pardon, and mean there may be not listed elements other key elements.

In view of it will be clear that, realize several targets of the disclosure above and obtain other favorable outcomes.

Because various changes can be carried out to above product and method in the case of without departing substantially from the scope of the present disclosure, It is expected that all the elements contained in above description all should be interpreted that illustrative and not have a limited significance.

Claims

1. a kind of formula (Ia) or (Ib) 3,5- bis- substitute 1,2,4- oxadiazoles or the method for its salt,

Methods described is following including making respectively：The N- hydroxyamidines or its tautomeric form of formula (IIa) or (IIb),

Respectively with formula (IIIa) or the acyl chlorides of (IIIb),

Reacted in the reactant mixture comprising organic phase and aqueous phase, the reactant mixture has comprising not miscible with water Solvent and the highly basic completely or almost completely decomposed in water, wherein the temperature of the reactant mixture is no more than 85 DEG C；

And wherein Ar¹Selected from the group consisted of：Phenyl, pyridine radicals, pyrazolyl, oxazolyl Huo isoxazolyls, it each may be used To be optionally independently substituted by one or more substituents, the substituent is selected from the group consisted of：Halogen, CF₃, alkane Base, OCF₃、OCH₃, CN and C (H) O；And

Ar²Selected from the group consisted of：Thienyl, furyl, oxazolyl Huo isoxazolyls, it each can be optionally independent Ground is substituted by one or more substituents, and the substituent is selected from the group consisted of：Fluorine, chlorine, CH₃And OCF₃,

The pH of wherein described aqueous phase is at least 9.

2. according to the method for claim 1, wherein methods described includes making the N- hydroxyamidines or its tautomerism of formula (IIa) The acyl chloride reaction of form and formula (IIIa) substitutes 1,2,4- oxadiazoles or its salt to form the 3,5- bis- of formula (Ia).

3. according to the method for claim 1, wherein methods described includes making the N- hydroxyamidines or its tautomerism of formula (IIb) The acyl chloride reaction of form and formula (IIIb) substitutes 1,2,4- oxadiazoles or its salt to form the 3,5- bis- of formula (Ib).

4. method according to claim 1, wherein 3, the 5- bis- substitutes 1,2,4- oxadiazoles to be 3- phenyl -5- (2- thiophene Base) -1,2,4- oxadiazoles.

5. the method according to any one of claim 1 to 4, wherein the reactant mixture is further urged comprising phase transfer Agent.

6. method according to claim 5, wherein the phase transfer catalyst is selected from group consisting of：Quaternary ammonium salt, phosphonium salts and Crown ether.

7. method according to claim 5, wherein the phase transfer catalyst is selected from the group consisted of：Tetrabutylammonium hydroxide Ammonium, TBAB, tetrabutyl ammonium fluoride, tetrabutylammonium iodide, Si butyl phosphonium bromide, 4-butyl phosphonium chloride and benzyl three Ammonium hydroxide.

8. method according to claim 5, wherein the phase transfer catalyst is TBAH.

9. the method according to any one of claim 1 to 4, wherein it is described can not organic solvent miscible with water make it is described N- hydroxyamidines and the 3,5- bis- substitute -1,2,4- oxadiazoles to dissolve.

10. the method according to any one of claim 1 to 4, wherein the organic solvent and water that can not be miscible with water Form azeotropic mixture.

11. the method according to any one of claim 1 to 4, wherein it is described can not organic solvent miscible with water be selected from The group consisted of：2- methyltetrahydrofurans and butyl acetate.

12. according to the method for claim 11, wherein it is described can not organic solvent miscible with water be 2- methyl tetrahydrochysene furans Mutter.

13. the method according to any one of claim 1 to 4, wherein the highly basic is selected from the group consisted of：Hydrogen-oxygen Change sodium, potassium hydroxide, lithium hydroxide and calcium hydroxide.

14. method according to claim 13, wherein the highly basic is selected from the group consisted of：Sodium hydroxide and hydroxide Potassium.

15. the method according to any one of claim 1 to 4, wherein the pH of the aqueous phase is at least 10.

16. the method according to any one of claim 1 to 4, wherein the pH of the aqueous phase is 12-13.

17. the method according to any one of claim 1 to 4, wherein by add it is extra in water completely or nearly The highly basic decomposed completely increases or maintained the pH of the aqueous phase into the reactant mixture.

18. the method according to any one of claim 1 to 4, wherein the temperature of the reactant mixture is maintained into 55 DEG C at 75 DEG C.

19. the method according to any one of claim 1 to 4, wherein make the N- hydroxyamidines be dissolved in it is described can not be with In the miscible organic solvent of water, the acyl chlorides is then added to form the reactant mixture.

20. the method according to any one of claim 1 to 4, it further comprises removing from the reactant mixture After organic solvent not miscible with water described at least a portion, mixed with the precipitated form from water layer from the reaction Thing reclaims the 3,5- bis- and substitutes -1,2,4- oxadiazoles.

21. according to the method for claim 20, it further comprises adding surfactant into the reactant mixture.

22. according to the method for claim 21, wherein the surfactant being added in the reactant mixture makes The 3,5- bis- substitute the drop of -1,2,4- oxadiazoles be dissolved in water layer and so that the drop solidifiable without being agglomerated into Larger drop.

23. according to the method for claim 21, wherein can not described at least a portion being removed from the reactant mixture Before organic solvent miscible with water, the surfactant is added into the reactant mixture.

24. according to the method for claim 21, add the surface-active wherein after the reaction essentially completes Agent is into the reactant mixture.

25. according to the method for claim 21, wherein the surfactant is selected from the group consisted of：Anion or Nonionic surfactant and its combination.

26. the method according to any one of claim 1 to 4, wherein the N- hydroxyamidines and the acyl chlorides is described anti- Production (IVa) or oxime ester intermediate, its salt or its tautomeric form of (IVb) are answered,

Wherein Ar¹And Ar²As defined in claim 1.

27. according to the method for claim 26, wherein it is described can not organic solvent miscible with water make the N- hydroxyamidines, Oxime ester intermediate and the 3,5- bis- substitution 1,2,4- the oxadiazole dissolvings.

28. according to the method for claim 26, wherein separating the oxime ester intermediate, subsequently form 3, the 5- bis- and substitute 1,2,4- oxadiazoles.

29. the method according to any one of claim 1 to 4, wherein the N- hydroxyamidines is substituted or not by making The benzoyl amidoxime that substituted benzonitrile is reacted and formed in the alcoholic solvent with sodium hydroxide with hydroxylamine hydrochloride, And the benzoyl amidoxime is separated from the alcoholic solvent, and be then dissolved in the solvent selected from the group consisted of In：2- methyltetrahydrofurans and butyl acetate.

30. the method according to any one of claim 1 to 4, wherein the N- hydroxyamidines is substituted or not by making Substituted benzonitrile and azanol reaction and the benzoyl amidoxime formed, and be dissolved in formed benzoyl amidoxime and be selected from In the solvent of the group consisted of：2- methyltetrahydrofurans and butyl acetate.

31. according to the method for claim 30, wherein being arrived to form the reaction of the benzoyl amidoxime at 20 DEG C Carried out at a temperature of 75 DEG C.

32. the method according to any one of claim 1 to 4, wherein the N- hydroxyamidines is substituted or not by making The benzoyl amidoxime that substituted benzonitrile combines with aqueous hydroxylamine solution and reacts and formed.

33. according to the method for claim 32, wherein the substituted or unsubstituted benzonitrile and aqueous hydroxylamine solution Merging in the absence of organic solvent the following group not miscible with water and reacting.

34. according to the method for claim 32, wherein the substituted or unsubstituted benzonitrile and aqueous hydroxylamine solution Combine and react in organic solvent not miscible with water, and the benzoyl amidoxime is dissolved in the solvent.

35. the method according to claim 11, consisted of wherein the organic solvent that can not be miscible with water is selected from Group：2- methyltetrahydrofurans and butyl acetate.

36. the method according to any one of claim 1 to 4, wherein methods described include：

(1) the N- hydroxyamidines is incorporated into reaction with the solution form being dissolved in the organic solvent not miscible with water In container；

(2) highly basic and optionally phase transfer catalyst completely or almost completely decomposed in water described in an addition part is described in In reaction vessel；

(3) acyl chlorides is added into the reaction vessel to form the reactant mixture；With

(4) reaction mixing in the extra highly basic completely or almost completely decomposed in water to the reaction vessel of addition In thing.

37. the method according to claim 11, consisted of wherein the organic solvent that can not be miscible with water is selected from Group：2- methyltetrahydrofurans and butyl acetate.

38. according to the method for claim 36, wherein add simultaneously the acyl chlorides with it is described it is extra in water completely or The highly basic almost decomposed completely is into the reaction vessel.

39. according to the method for claim 36, wherein sequentially add the acyl chlorides with it is described it is extra in water completely or The highly basic almost decomposed completely is into the reaction vessel.

40. the method according to any one of claim 1 to 4, wherein Ar¹It is unsubstituted phenyl.

41. the method according to any one of claim 1 to 4, wherein Ar¹It is the phenyl being mono-substituted, wherein the substitution Base is halogen.

42. the method according to any one of claim 1 to 4, wherein Ar¹It is by dibasic chlorine alkyl phenyl.

43. the method according to any one of claim 1 to 4, wherein Ar²It is substituted or unsubstituted thiophene or furan Mutter.

44. according to the method for claim 43, wherein Ar²It is unsubstituted thiophene.

45. according to the method for claim 29, wherein the alcoholic solvent is methanol.

46. according to the method for claim 2, wherein the acyl chlorides of the formula (IIIa) is prepared by 2- thiophenic acids.

47. according to the method for claim 46, wherein the acyl chlorides of the formula (IIIa) is 2 thiophen carbonyl chloride.

48. according to the method for claim 47, wherein the 2- thiophenic acids are by 2- acetyl thiophenes or 2 thiophene carboxaldehyde Prepare.

49. according to the method for claim 48, wherein the 2- thiophenic acids are prepared by 2- acetyl thiophenes.

50. according to the method for claim 49, wherein the 2- acetyl thiophenes are prepared by thiophene.

51. according to the method for claim 48, wherein the 2- thiophenic acids are prepared by 2 thiophene carboxaldehyde.

52. method according to claim 51, wherein the 2 thiophene carboxaldehyde is prepared by thiophene.

53. according to the method for claim 47, wherein 3, the 5- bis- of the formula (Ia) substitutes -1,2,4- oxadiazoles to be 3- benzene Base -5- (2- thienyls) -1,2,4- oxadiazoles or its salt.

54. the method according to any one of claim 46 to 53, wherein the reactant mixture further turns comprising phase Shifting catalyst.

55. the method according to any one of claim 46 to 53, wherein it is described can not organic solvent miscible with water make The N- hydroxyamidines and the 3,5- bis- substitute -1,2,4- oxadiazoles to dissolve.

56. the method according to any one of claim 46 to 53, wherein the organic solvent that can not be miscible with water with Water forms azeotropic mixture.

57. the method according to any one of claim 46 to 53, wherein the organic solvent choosing that can not be miscible with water Free group consisting of：2- methyltetrahydrofurans and butyl acetate.

58. the method according to any one of claim 46 to 53, wherein make the N- hydroxyamidines be dissolved in it is described can not In organic solvent miscible with water, the acyl chlorides is then added to form the reactant mixture.

59. method according to claim 53, it further comprises removing at least a portion from the reactant mixture After the organic solvent not miscible with water, with described in the precipitated form from water layer from reactant mixture recovery 3,5- bis- substitutes -1,2,4- oxadiazoles.

60. the method according to any one of claim 46 to 53, wherein the N- hydroxyamidines and the acyl chlorides is described Oxime ester intermediate, its salt or its tautomeric form of reacting generating (IVa),

Wherein

Ar¹Selected from the group consisted of：Phenyl, pyridine radicals, pyrazolyl, oxazolyl Huo isoxazolyls, it each can be optionally Independently it is substituted by one or more substituents, the substituent is selected from the group consisted of：Halogen, CF₃, alkyl, OCF₃、 OCH₃, CN and C (H) O；And

Ar²Selected from the group consisted of：Thienyl, furyl, oxazolyl Huo isoxazolyls, it each can be optionally independent Ground is substituted by one or more substituents, and the substituent is selected from the group consisted of：Fluorine, chlorine, CH₃And OCF₃。

61. method according to claim 60, wherein separating the oxime ester intermediate, the 3 of the formula (Ia) is subsequently formed, 5- bis- substitutes 1,2,4- oxadiazoles.

62. the method according to any one of claim 46 to 53, wherein the N- hydroxyamidines be by make it is substituted or Unsubstituted benzonitrile and azanol reaction and the benzoyl amidoxime formed, and formed benzoyl amidoxime is dissolved in choosing In the solvent of free group consisting of：2- methyltetrahydrofurans and butyl acetate.

63. method according to claim 62, wherein being arrived to form the reaction of the benzoyl amidoxime at 20 DEG C Carried out at a temperature of 75 DEG C.

64. the method according to any one of claim 46 to 53, wherein the organic solvent choosing that can not be miscible with water Free group consisting of：2- methyltetrahydrofurans and butyl acetate.

65. the method according to any one of claim 46 to 53, wherein methods described include：

(3) 2 thiophen carbonyl chloride is added into the reaction vessel to form the reactant mixture；With